药学学报, 2016, 51(6): 913-918
引用本文:
李文静, 李健蕊, 黄梦昊, 吴舟一, 陈金花, 李虎, 吕晓芹, 程军军, 彭宗根. 细胞角蛋白8对丙型肝炎病毒复制的影响[J]. 药学学报, 2016, 51(6): 913-918.
LI Wen-jing, LI Jian-rui, HUANG Meng-hao, WU Zhou-yi, CHEN Jin-hua, LI Hu, L� Xiao-qin, CHENG Jun-jun, PENG Zong-gen. The influence of intracellular keratin 8 on hepatitis C virus replication[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 913-918.

细胞角蛋白8对丙型肝炎病毒复制的影响
李文静, 李健蕊, 黄梦昊, 吴舟一, 陈金花, 李虎, 吕晓芹, 程军军, 彭宗根
中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
摘要:
细胞角蛋白8(KRT-8)水平在丙型肝炎病毒(HCV)感染引起的肝癌患者体内及在HCV感染细胞培养中均明显上升,与肝病进展密切相关,但KRT-8是否对HCV复制产生影响并不清楚。本文利用KRT-8高表达质粒和特异性shRNA分析其在细胞培养中对HCV复制的影响,并分析低沉默KRT-8后与已知抗HCV药物联合抑制HCV的作用及其对常见HCV耐药突变株的影响。结果显示,胞内KRT-8水平随HCV复制的增加而增加,其高表达能促进HCV的复制,而特异性干扰KRT-8基因表达后, HCV的复制受到抑制。低沉默KRT-8可以增强已知抗HCV药物特拉匹韦抑制HCV复制的作用,且对蛋白酶抑制剂常见耐药突变(A156T和D168V) HCV也具有抑制作用。这提示KRT-8可能是HCV复制的辅助因子,下调KRT-8具有抗HCV的作用及优势。因此, KRT-8有望成为抗HCV药物研发的一个新的宿主靶点。
关键词:    细胞角蛋白8      丙型肝炎病毒      辅助因子      抗病毒靶点      宿主成分     
The influence of intracellular keratin 8 on hepatitis C virus replication
LI Wen-jing, LI Jian-rui, HUANG Meng-hao, WU Zhou-yi, CHEN Jin-hua, LI Hu, L� Xiao-qin, CHENG Jun-jun, PENG Zong-gen
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
The level of intracellular keratin 8(KRT-8) is associated with liver diseases, whose expression is increased in hepatitis C virus (HCV)-infected patients with hepatocarcinoma and in cultural cells infected with HCV. However, it is not clear whether KRT-8 will impact HCV replication. In this paper, the HCV replication was analyzed in response to high expression and silence of KRT-8. The inhibitory activities against wild-type and mutant HCV were also analyzed by silence of KRT-8 or combined with known anti-HCV drug telaprevir. Results showed that the protein level of KRT-8 was increased in proportion with the HCV replication. The high expression was found to facilitate HCV replication, while the silence of KRT-8 was able to inhibit HCV replication and enhanced the anti-HCV activity of telaprevir. It also inhibited A156T and D168V mutant HCV, which are resistant to protease inhibitors. These results suggest that KRT-8 is a co-factor for HCV replication. Down-regulation of KRT-8 can inhibit wild type and mutant HCV replication to enhance the anti-HCV activity of known anti-HCV drugs. Therefore, KRT-8 may be a new target in the development of anti-HCV agents.
Key words:    keratin 8    hepatitis C virus    co-factor    antiviral target    host factor   
收稿日期: 2016-03-28
DOI: 10.16438/j.0513-4870.2016-0283
基金项目: 国家自然科学基金优秀青年科学基金资助项目(81322050);教育部新世纪优秀人才项目(NCET-12-0072).
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